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Experimental evidence indicates that exposure to certain pollutants is associated with liver damage. Per- and polyfluoroalkyl substances (PFAS) are persistent synthetic chemicals widely used in industry and consumer products and bioaccumulate in food webs and human tissues, such as the liver. The objective of this study was to conduct a systematic review of the literature and meta-analysis evaluating PFAS exposure and evidence of liver injury from rodent and epidemiological studies. PubMed and Embase were searched for all studies from earliest available indexing year through 1 December 2021 using keywords corresponding to PFAS exposure and liver injury. For data synthesis, results were limited to studies in humans and rodents assessing the following indicators of liver injury: serum alanine aminotransferase (ALT), nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, or steatosis. For human studies, at least three observational studies per PFAS were used to conduct a weighted -score meta-analysis to determine the direction and significance of associations. For rodent studies, data were synthesized to qualitatively summarize the direction and significance of effect. Our search yielded 85 rodent studies and 24 epidemiological studies, primarily of people from the United States. Studies focused primarily on legacy PFAS: perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorononanoic acid (PFNA), and perfluorohexanesulfonic acid. Meta-analyses of human studies revealed that higher ALT levels were associated with exposure to PFOA ( 6.20, ), PFOS ( 3.55, ), and PFNA ( 2.27, ). PFOA exposure was also associated with higher aspartate aminotransferase and gamma-glutamyl transferase levels in humans. In rodents, PFAS exposures consistently resulted in higher ALT levels and steatosis. There is consistent evidence for PFAS hepatotoxicity from rodent studies, supported by associations of PFAS and markers of liver function in observational human studies. This review identifies a need for additional research evaluating next-generation PFAS, mixtures, and early life exposures. https://doi.org/10.1289/EHP10092.

Exposure to per- and polyfluoroalkyl substances (PFAS), a prevalent class of persistent pollutants, may increase the risk of type 2 diabetes. We examined associations between PFAS exposure and glucose metabolism in youth. Overweight/obese adolescents from the Study of Latino Adolescents at Risk of Type 2 Diabetes (SOLAR; ) participated in annual visits for an average of . Generalizability of findings were tested in young adults from the Southern California Children's Health Study (CHS; ) who participated in a clinical visit with a similar protocol. At each visit, oral glucose tolerance tests were performed to estimate glucose metabolism and function via the insulinogenic index. Four PFAS were measured at baseline using liquid chromatography-high-resolution mass spectrometry; high levels were defined as concentrations percentile. In females from the SOLAR, high perfluorohexane sulfonate (PFHxS) levels ( ) were associated with the development of dysregulated glucose metabolism beginning in late puberty. The magnitude of these associations increased postpuberty and persisted through 18 years of age. For example, postpuberty, females with high PFHxS levels had higher 60-min glucose (95% CI: ; ), higher 2-h glucose (95% CI: ; ), and 25% lower function ( ) compared with females with low levels. Results were largely consistent in the CHS, where females with elevated PFHxS levels had higher 60-min glucose (95% CI: ; ) and higher 2-h glucose, which did not meet statistical significance (95% CI: ; ). In males, no consistent associations between PFHxS and glucose metabolism were observed. No consistent associations were observed for other PFAS and glucose metabolism. Youth exposure to PFHxS was associated with dysregulated glucose metabolism in females, which may be due to changes in function. These associations appeared during puberty and were most pronounced postpuberty. https://doi.org/10.1289/EHP9200.

Childhood obesity poses a significant public health challenge, yet the molecular intricacies underlying its pathobiology remain elusive. Leveraging extensive multi-omics profiling (methylome, miRNome, transcriptome, proteins and metabolites) and a rich phenotypic characterization across two parts of Europe within the population-based Human Early Life Exposome project, we unravel the molecular landscape of childhood obesity and associated metabolic dysfunction. Our integrative analysis uncovers three clusters of children defined by specific multi-omics profiles, one of which characterized not only by higher adiposity but also by a high degree of metabolic complications. This high-risk cluster exhibits a complex interplay across many biological pathways, predominantly underscored by inflammation-related cascades. Further, by incorporating comprehensive information from the environmental risk-scape of the critical pregnancy period, we identify pre-pregnancy body mass index and environmental pollutants like perfluorooctanoate and mercury as important determinants of the high-risk cluster. Overall, our work helps to identify potential risk factors for prevention and intervention strategies early in the life course aimed at mitigating obesity and its long-term health consequences. Obesity encompasses numerous interconnected pathological mechanisms. Here, the authors show that integrating multi-omics data uncovers distinct molecular profiles and prenatal factors linked to childhood obesity and metabolic dysfunction, providing insights for early prevention and intervention strategies.

Background Ultra-processed foods (UPFs), often high in sodium, sugar, and unhealthy fats, compose more than half of total dietary energy consumption in the United States. A diet composed of a high amount of UPFs can contribute to glucose dysregulation and insulin resistance, which may lead to prediabetes and type 2 diabetes (T2D). However, few studies have assessed the associations between UPFs and T2D or obesity in young people. The goal of this study is to examine associations between UPF consumption and prediabetes and related biomarkers in youth. Methods Young adults (age 17–22, n  = 85) with a history of overweight or obesity from the Metabolic and Asthma Incidence Research (Meta-AIR) study, a subset of the Children’s Health Study, were enrolled between 2014 and 2018 and returned for a second visit between 2020 and 2022. Participants completed two 24-hour dietary recalls and an oral glucose tolerance test at each visit. Food items were categorized as either an UPF or non-UPF according to NOVA classification guidelines. The proportion of the diet composed of UPFs was calculated for each participant. Regression models were used to assess relationships of UPF consumption at baseline and change between visits with markers of glucose homeostasis at follow-up, adjusting for demographics, physical activity, and total energy intake. Results A 10%-point increase in UPF consumption between visits was associated with a 51% (OR: 1.51, 95% Cl: 1.04, 2.31) higher odds of having prediabetes and 158% (OR: 2.58, 95% CI: 1.43, 5.85) higher odds of impaired glucose tolerance at follow-up. Higher baseline UPF consumption was significantly positively associated with 2-hour insulin ( = 45.11, 95% CI: 22.42, 67.80) and insulin area under the curve ( = 63.56, 95% CI: 34.95, 92.17) at follow-up. Conclusion UPF consumption may increase the risk for T2D among young adults. Our findings suggest that limiting UPF consumption could be an important strategy for T2D prevention in this population.

Background Obesity and neurodevelopmental delay are complex traits that often co-occur and differ between boys and girls. Prenatal exposures are believed to influence children’s obesity, but it is unknown whether exposures of pregnant mothers can confer a different risk of obesity between sexes, and whether they can affect neurodevelopment. Methods We analyzed data from 1044 children from the HELIX project, comprising 93 exposures during pregnancy, and clinical, neuropsychological, and methylation data during childhood (5–11 years). Using exposome-wide interaction analyses, we identified prenatal exposures with the highest sexual dimorphism in obesity risk, which were used to create a multiexposure profile. We applied causal random forest to classify individuals into two environments: E1 and E0. E1 consists of a combination of exposure levels where girls have significantly less risk of obesity than boys, as compared to E0, which consists of the remaining combination of exposure levels. We investigated whether the association between sex and neurodevelopmental delay also differed between E0 and E1. We used methylation data to perform an epigenome-wide association study between the environments to see the effect of belonging to E1 or E0 at the molecular level. Results We observed that E1 was defined by the combination of low dairy consumption, non-smokers’ cotinine levels in blood, low facility richness, and the presence of green spaces during pregnancy (OR interaction  = 0.070, P  = 2.59 × 10 −5 ). E1 was also associated with a lower risk of neurodevelopmental delay in girls, based on neuropsychological tests of non-verbal intelligence (OR interaction  = 0.42, P  = 0.047) and working memory (OR interaction  = 0.31, P  = 0.02). In line with this, several neurodevelopmental functions were enriched in significant differentially methylated probes between E1 and E0. Conclusions The risk of obesity can be different for boys and girls in certain prenatal environments. We identified an environment combining four exposure levels that protect girls from obesity and neurodevelopment delay. The combination of single exposures into multiexposure profiles using causal inference can help determine populations at risk.

Background/objective There is limited knowledge on how diet affects the epigenome of children. Ultra-processed food (UPF) consumption is emerging as an important factor impacting health, but mechanisms need to be uncovered. We therefore aimed to assess the association between UPF consumption and DNA methylation in children. Methods We conducted a meta-analysis of epigenome-wide association studies (EWAS) from a total of 3152 children aged 5–11 years from four European studies (HELIX, Generation XXI, ALSPAC, and Generation R). UPF consumption was defined applying the Nova food classification system (group 4), and DNA methylation was measured in blood with Illumina Infinium Methylation arrays. Associations were estimated within each cohort using robust linear regression models, adjusting for relevant covariates, followed by a meta-analysis of the resulting EWAS estimates. Results Although no CpG was significant at FDR level, we found suggestive associations ( p -value < 10 –5 ) between UPF consumption and methylation at seven CpG sites. Three of them, cg00339913 (PHYHIP), cg03041696 (intergenic), and cg03999434 (intergenic), were negatively associated, whereas the other four, cg14665028 (NHEJ1), cg18968409 (intergenic), cg24730307 (intergenic), and cg09709951 (ATF7), were positively associated with UPF intake. These CpGs have been previously associated with health outcomes such as carcinomas, and the related genes are mainly involved in pathways related to thyroid hormones and liver function. Conclusion We only found suggestive changes in methylation at 7 CpGs associated with UPF intake in a large EWAS among children: although this shows a potential impact of UPF intake on DNAm, this might not be a key mechanism underlying the health effects of UPFs in children. There is a need for more detailed dietary assessment in children studies and of intervention studies to assess potential epigenetic changes linked to a reduction in UPF in the diet. Graphical abstract

Polymorphic genomic inversions are chromosomal variants with intrinsic variability that play important roles in evolution, environmental adaptation, and complex traits. We investigated the DNA methylation patterns of three common human inversions, at 8p23.1, 16p11.2, and 17q21.31 in 1,009 blood samples from children from the Human Early Life Exposome (HELIX) project and in 39 prenatal heart tissue samples. We found inversion-state specific methylation patterns within and nearby flanking each inversion region in both datasets. Additionally, numerous inversion-exposure interactions on methylation levels were identified from early-life exposome data comprising 64 exposures. For instance, children homozygous at inv-8p23.1 and higher meat intake were more susceptible to TDH hypermethylation ( P  = 3.8 × 10 −22 ); being the inversion, exposure, and gene known risk factors for adult obesity. Inv-8p23.1 associated hypermethylation of GATA4 was also detected across numerous exposures. Our data suggests that the pleiotropic influence of inversions during development and lifetime could be substantially mediated by allele-specific methylation patterns which can be modulated by the exposome. Analysis of the relationship between presence of common DNA sequence inversions and DNA methylation patterns suggests a role for environmental exposures (such as food intake) in mediating inversion state-specific methylation patterns.

ObjectivesMaternal pre-pregnancy weight is known to affect foetal development. However, it has not yet been clarified if gestational weight gain is associated with childhood behavioural development.MethodsWe performed a pooled analysis of two prospective birth cohorts to investigate the association between gestational weight gain and childhood problem behaviours, and the effect modification of maternal pre-pregnancy BMI. In total, 378 mother–child pairs from the Maastricht Essential Fatty Acids Birth cohort (MEFAB) and 414 pairs from the Rhea Mother–Child cohort were followed up from early pregnancy to 6–7 years post-partum. At follow up, parents assessed their children’s behaviour, measured as total problems, internalizing and externalizing behaviours, with the Child Behaviour Checklist. We computed cohort- and subject-specific gestational weight gain trajectories using mixed-effect linear regression models. Fractional polynomial regressions, stratified by maternal pre-pregnancy BMI status, were then used to examine the association between gestational weight gain and childhood problem behaviours.ResultsIn the pre-pregnancy overweight/obese group, greater gestational weight gain was associated with higher problem behaviours. On average, children of women with overweight/obesity who gained 0.5 kg/week scored 25 points higher (on a 0–100 scale) in total problems and internalizing behaviours, and about 18 points higher in externalizing behaviours than children whose mothers gained 0.2 kg/week. Inconsistent results were found in the pre-pregnancy normal weight group.Conclusions for PracticeExcessive gestational weight gain in women with pre-pregnancy overweight/obesity might increase problem behaviours in school-age children. Particular attention should be granted to avoid excessive weight gain in women with a pre-pregnancy overweight or obesity.

Lower prenatal exposure to n-3 PUFA relative to n-6 PUFA has been hypothesised to influence allergy development, but evidence remains largely inconsistent. In the Dutch Maastricht Essential Fatty Acid Birth (MEFAB) (n 293) and Greek RHEA Mother–Child (n 213) cohorts, we investigated whether cord blood phospholipid PUFA concentrations are associated with symptoms of wheeze, asthma, rhinitis and eczema at the age of 6–7 years. Information on allergy-related phenotypes was collected using validated questionnaires. We estimated relative risks (RR) and 95 % CI for associations of PUFA with child outcomes using multivariable generalised linear regression models. In pooled analyses, higher concentration of the n-3 long-chain EPA and DHA and a higher total n-3:n-6 PUFA ratio were associated with lower risk of current wheeze (RR 0·61; 95 % CI 0·45, 0·82 per sd increase in EPA+DHA and 0·54; 95 % CI 0·39, 0·75 per unit increase in the n-3:n-6 ratio) and reduced asthma risk (RR 0·50; 95 % CI 0·31, 0·79 for EPA+DHA and 0·43; 95 % CI 0·26, 0·70 for the n-3:n-6 ratio). No associations were observed for other allergy-related phenotypes. The results were similar across cohorts. In conclusion, higher EPA and DHA concentrations and a higher n-3:n-6 fatty acid ratio at birth were associated with lower risk of child wheeze and asthma. Our findings suggest that dietary interventions resulting in a marked increase in the n-3:n-6 PUFA ratio, and mainly in n-3 long-chain PUFA intake in late gestation, may reduce the risk of asthma symptoms in mid-childhood.

Background: The rising prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), particularly among pediatric populations, requires identification of modifiable risk factors to control disease progression. Per- and polyfluoroalkyl substances (PFAS) have emerged as potential contributors to liver damage; however, their role in MASLD remains underexplored. This study aimed to develop a translational framework integrating human and in vitro data to elucidate the effect of PFAS on MASLD development. Methods: We measured PFAS plasma levels in the Teen-LABS cohort ( n  = 136), comprising adolescents with obesity (mean age = 16.8 years) undergoing bariatric surgery. Plasma samples were also analyzed using proteomic and metabolomic assays. MASLD was diagnosed by liver biopsy examination. Human liver spheroids were exposed to perfluoroheptanoic acid (PFHpA) in vitro and analyzed by single-cell transcriptomics. The latent unknown clustering with integrated data (LUCID) model was employed to assess associations between PFHpA exposure, multiomic signatures, and MASLD risk. Results: Here we show that, among all PFAS measured, doubling of PFHpA levels is associated with an 80% higher MASLD risk (OR, 1.8; 95% CI: 1.3–2.5). Integrated human and in vitro analyses suggest dysregulation of pathways involved in inflammation and lipid metabolism. A distinct proteome profile is associated with significantly higher odds of MASLD (OR = 7.1). Conclusions: This study offers evidence implicating PFHpA, a short-chain unregulated PFAS congener, in MASLD development in adolescents, and highlights the critical role of protein dysregulation in disease pathogenesis. The molecular mechanisms identified here can inform the development of targeted prevention and treatment strategies. Baumert, Maretti-Mira et al. integrate human epidemiological data and in vitro liver spheroid models to investigate PFHpA, an unregulated PFAS, in adolescent MASLD. Findings link PFHpA exposure to increased disease risk and identify key pathogenic mechanisms and potential therapeutic targets. Plain Language Summary Metabolic dysfunction–associated steatotic liver disease (MASLD) is a form of fatty liver disease not caused by heavy alcohol use. It includes a more severe condition, MASLD-associated steatohepatitis (MASH), where liver inflammation and damage occur. The growing number of children affected by MASLD highlights the urgent need to identify environmental and lifestyle factors that may worsen the disease. This study examined the role of perfluoroheptanoic acid (PFHpA), a type of per- and polyfluoroalkyl substance (PFAS), in MASLD. PFAS are man-made chemicals widely used by industrial processes and consumer products, and nearly everyone in the United States has detectable levels of PFAS in their blood. We found that higher PFHpA levels were linked to greater risk of MASLD and worsen disease severity. These findings provide important evidence for researchers, clinicians, and public health officials. Understanding how PFAS contribute to liver disease may help shape prevention strategies, guide policies that limit exposure, and support precision health approaches to protect children and other vulnerable groups.